This invention relates to materials and methods for screening chemical compounds for potential pharmaceutical activity, and more specifically to an assay for soluble compounds, wherein the compounds are delivered to the assay in a form of a coating on solid phase particles carrying microtransponders. The coating is dissolved and the compounds are released just prior to or during the assay, and the identity of the compound is provided by the serial number encoded on the transponder.
Libraries of chemical compounds in possession of large pharmaceutical companies have more than 100,000 individual compounds. The advent of combinatorial chemistry for the synthesis of compound has accelerated the growth of the number of compounds in libraries. It is anticipated that within a few years the size of the largest libraries of individual chemical compounds will approach or even exceed 10.sup.6.
The number of macromolecular targets of interest, such as receptors, enzymes or proteins, is rapidly growing as well, due to the progress with rapid methods to sequence genes, to classify the genes and proteins, to predict the structure of proteins, and to analyze their function. The human genome project is a significant factor contributing to the rapid growth of the number of targets of interest.
The growth of the number of chemical compounds and the number of targets create a need for rapid methods to analyze the properties of the compounds from chemical libraries with respect to the macromolecular targets. The methods currently being used rely on robotics and automation to dispense, dissolve, aliquot, mix and analyze the compounds. The automated systems are complex due to the number of vessels and transfer steps.
The subject of this invention is a method to tag soluble chemical compounds to minimize the number of handling steps and the complexity of handling the compounds, and to reduce the time needed for the analysis of the library. The above improvements will also enable small laboratories which do not have the sophisticated automated systems to perform the screening, since according to the present invention, inexpensive and readily available instrumentation should suffice.
In a preferred implementation of this invention, a transponder is used as a carrier for the drug. A transponder is a radio transmitter-receiver activated for transmission of data by reception of a predetermined signal, and may also be referred to as a microtransponder, radiotransponder, radio tag, transceiver, etc. The signal comes from a dedicated scanner, which also receives and processes the data sent by the transponder in response to the signal. The scanner function can be combined with the write function, i.e. the process of encoding the data on the transponder. Such a combination instrument is called a scanner read/write device. An advantage of the transponder-scanner system stems from the fact the two units are not physically connected by wire, but are coupled inductively, i.e. by the use of electromagnetic radiation, typically in the range from 5-1,000 kHz, but also up to 1 GHz and higher.
Several transponders currently available commercially have been described in four previous patent applications, Case No. 7295/4, 7295/5, 7295/9, 7295/10 (Brinks Hofer Gilson & Lione, Chicago). They include Bio Medic Data Systems' (BMDS, 255 West Spring Valley Ave., Maywood, N.J.) programmable transponder for use in laboratory animal identification. The transponder is implanted in the body of an animal, such as a mouse, and is glass-encapsulated to protect the electronics inside the transponder from the environment. One of the transponders manufactured by this corporation, model# IPTT-100, has dimensions of 14.times.2.2.times.2.2 mm and weighs 120 mg. The transponder is user-programmable with up to 16 alphanumeric characters, the 16th letter programmable independently of the other 15 letters, and has a built-in temperature sensor as well. The electronic animal monitoring system (ELAMS) includes also a scanner read/write system to encode or read data on/from the transponder. The construction of the transponder and scanner is described in U.S. Pat. Nos. 5,250,944, 5,252,962 and 5,262,772, the disclosures of which are incorporated herein by reference. Other similar transponder-scanner systems include a multi-memory electronic identification tag (U.S. Pat. No. 5,257,011) manufactured by AVID Corporation (Norco, Calif.) and a system made by TEMIC-Telefunken (Eching, Germany). AVID's transponder has dimensions of 1 mm.times.1 mm.times.11 mm, and can encode 96 bits of information, programmed by the user. The present invention can be practiced with different transponders, which might be of different dimensions and have different electronic memory capacity.
Transponders of the type discussed above have been disclosed for use in drug discovery by Mandecki (see patent applications listed above) and have been used for solid phase synthesis of compounds followed by screening in an assay for a pharmaceutically relevant biological activity (Moran, E. J. et al. 1995, Radio frequency tag encoded combinatorial library method for the discovery of tripeptide-substituted cinnamic acid inhibitors of the protein tyrosine phosphatase PTB1B. J. Am. Chem. Soc. 117, 10787-10788; Service, R. F. 1995, Radio tags speed compound synthesis (an editorial). Science 270, p. 577). In both of these applications the compounds were covalently and permanently linked to the transponders. According to the present invention, the compounds are only deposited (coated) on the surface of the transponders, and can undergo a dissolution under very mild conditions (simple exposure to buffers will suffice) without any changes of the chemical structure of the compounds. When dissolved, the compounds can be tested in assay configurations commonly used for testing soluble compounds.